Eugenol glycolic acid and isoeugenol glycolic acid amides



States Patent :The present invention is concerned with new derivatives of eugenol glycolic acid and isoeugenol glycolic acid [a-(2-methoxy-4-allyl-phenoxyyacetic acid or a-(2- methoxy- 4-propenyl-phnoxy)-acetic acid] and the production thereof. These "compounds have valuable therapeutical'properties.

:Eugen'ol xand isoeugenol glycolic acid amides substituted .ill the amide group by hydrocarbon radicals have not been known up to now. Surprisingly it has now been found that such compounds of the general formula:

on; B2 I wherein R- represents the allyl or propen-(l)-yl radical,

R represents an alkyl, alkenyl, cycloalkyl radical or a phenyl or benzyl radicalsubstituted if desired by halogen, low molecular alkyl or alkoxy groups, R represents hydrogen or an alkylor alkenyl radical, and alkyl radicals B and R may also be bound to each other direct or by way, of an 'oxygen atom, have valuable properties, in particular hypnoticfsedative, anticonvulsive and anaestheticiaetivitm which.are of therapeutical value.

."The compounds defined above can be produced by reacting eugenol or isoeugenol glycolic acid or a reactive functionaLderivative of these acids with a primary or secondary amine of the general formula:

H- N v V Ra 1 II I Suitable reactive functional derivativesof eugenol glycolicacid and isoeugenol glycolic acid are, for example, their halides and mixed anhydrides with low organic carboxylic acids, in particular acetic acid, as well as'the esters thereof, in particular the low alkyl esters and phenyl esters. The reactions are advantageously performed in solvents or 'diluents. Inert organic solvents such as ether orbenzene hydrocarbons on theone hand and, on the other handwater, are suitable solvents for the reactions with acid halides and anhydrides. Also alcohols can be used for the reactions with acid esters. In the reactions with acid halides or mixed anhydrides in organic solvents, an excess of the amine to be reacted or also. a tertiary organic base such as pyridine or dimethylaniline can be used as acid binding agent. When the reaction is performed in water, also inorganic substances such as sodium or potassium carbonate can be used as well.

a; Amodification' of the production process defined above B2 In Wherein'R has the meaning given above, and R has the meaning given above for R with the exception of hydrogen, with a salt of eugenol or iseugenol glycolic acid, in particular an alkali salt, the reaction being performed in the warm. The desired N.N-disubstituted amides are formed while carbon dioxide is generated and the corresponding chlorides,'e.g. alkali metal chlorides, are separated.

Partial hydrolysis of amidines of the general formula:

is another possibility for the production of the new amides according to the definition. The amidines themselves are obtained by methods known per se starting from eugenol glycolic acid nitrile and isoeugenol glycolic acid nitrile for example by converting these into iminoether hydrochlorides and reacting the latter with amines of the general Formula H.

Examples of starting materials of the general Formula II are: methylamine, ethylamine, -n-propylamine, isopr'opylam'ine, -n-butylaniine, isobutylamine, sec. butylamine, n-amylamine, isoamylamine, n-hexylamine, -allylarnine, methallylami'ne, cyclopentylamine, cyclohexylamine, cycloheptylamine, benzylamine, B-phehyl-ethyl amine, dimethylamine, methyl-ethylamine, diethylamine, methyl-n-propylamine, methyl-,isopropylamine, di-n-pro- 'pylamine, methyl-n-butylamine, methyl-isobutylamine,

di-n butylamine, di isobutylamine, methyl-allylarnine, ethyl-'allyl'amine, ldiall'ylamine, 'methyl-methallylami'n e, dirnefthallyl'amine, N-methyl-cyclohexylamine, N-methylbenzylainine, -p-;chloro-benzylamine, -p-methoxy-ben'zylamine, p-m etl1yl-benzylamine, dibenzylamine, pyrrolidine, piperidine, Z-m'ethyI-piperidine, morpholine and N- alkyl or N-alkenyl 'ar'ylamines such as N-methyl, N ethyl, N-n-propyl, N-isopropyl, N-nI-butyl, N-isobutyl, N-se'c'; but yl, N-n-amyl, N-isoamyl, N-n-hexyl, N-allyl, N-crotyl,

and'N-l'nthallyl aniline, -o-toluidine, -m-toluidiri'e, ptelui dine, -3. 4-dimethyl aniline, -2.4 -dimethyl aniline, 2.5 diniethyl aniline, -2.'6 -'dimethyl aniline, -mesidine, -4-ethyl aniline, -4-tert. butyl aniline, -2-chloraniline, -3-'cl'1loraniline, 4-chloraniline, -2.5-dichloraniline, -4-bromaniliiie, o-anisidin'e, -m-anisidine, -p-anisidine and p-phenetidine. Starting materials of the general Formula III are the carbaminyl chlorides derivedfrom the above secondary airlines. k

The following examples'further illustrate the produc"-' tionof the new compounds. Parts are given as parts by Weight and their relationship to parts by volume is as that of grammes to cubic centimetres. in degrees centigrade. I Example 1 g parts (:107 parts by volume) of freshly distilled thionyl chloride .aregradually added to 220 parts of anhydrous eugenol glycolic acid [ct-(2-methoxy-4-allyb phenoxy) acetic acid] in 1000 parts by volume of anliydrous benzene (acid containing crystalwater can'be pre-' viously dehydrated for example by distilling some hun dred parts of benzene), so that the temperature does not exceed 4050, the reaction mixture being cooled if necessary. I It is then boiled under reflux for about 30-40 minutes until no more hydrogen chloride is given off. benzene and excess thionyl chloride are then evaporated oflf in the vacuum. The residue, a dark yellow oil, is the The temperatures are Patented Nov. 3, 1959 chloride of eugenol glycolic acid which can be further reacted without any processing.

240 parts of the acid chloride obtained above are dissolved in 500 parts by volume of ether and 180 parts (=260 parts by volume) of anhydrous diethylamine are slowly added while stirring and cooling. The reaction is vigorous and the diethylaminehydrochloride immediately precipitates. On completion of the addition the whole is heated for 15 minutes at 40-50", the precipitated diethylamine hydrochloride is filtered oil under suction and washed twice with 50 parts by volume of ether each time. The ethereal solution of the diethylamide is Washed with 100 parts by volume of a sodium carbonate solution and then with water until the reaction is neutral. The solution is then dried with calcium chloride and filtered. The ether is evaporated ofi whereupon about 200 parts of crude diethylamide remain which are distilled in the vacuum. About 180 parts of eugenol glycolic acid diethylamide pass over between 188-195 under 2-3 mm. pressure. The product is a pale yellow oil which is insoluble in water but soluble in the majority of organic solvents.

' Example 2 On using 30 parts of 75% ethylamine solution, eugenol glycolic acid ethylamide is obtained in an analogous manner, M.P. 59-60.

Example 3 13 parts of n-propylamine are added dropwise while stirring and cooling with a cooling mixture to a solution of 24 parts of eugenol glycolic acid chloride in 100 parts by volume of abs. ether. On completion of the addition of the amine, the reaction mixture is boiled under reflux for about 1 /2 hours, it is then cooled and 100 parts of water are added. The ethereal solution is separated, washed with diluted sodium carbonate solution and water, dried and the solvent is distilled oif. On recrystallising the residue from petroleum ether, eugenol glycolic acidn-propyl amide is obtained. M.P. 44-45.

If instead of n-propoylamine, the same amount of isopropylamine or allylamine is used, then eugenol glycolic acid isopropylamide (M.P. 44-45 or eugenol glycolic acid allylamide (M.P. 54-55) is obtained in an analogous manner.

Starting from 15 parts of n-bntylamine, on evaporating off the ether according to the above method, a crude product is obtained from which eugenol glycolic acid-nbutylamide in a Hickmann flask passes over at l43145 under 0.003 mm. pressure. The product solidifies into a crystal mass which melts at about 40.

The following compounds can also be produced according to the method described in the above example by using: parts of cyclohexylamine, eugenol glycolic acid cyclohexylamide (M.P. 5556); 23 parts of cyclohexylmethylamine, eugenol glycolic acid cyclohexylmethyl amide (M.P. 67-68); 23 parts of N-methylcyclohexylamine, eugenol glycolic acid-N-methyl-cyclohexylamide (B.P. 169172); 22 parts of benzylamine, eugenol glycolic acid benzylamide (M.P. 51-52); 17 parts of piperidine, eugenol glycolic acid piperidide, a viscous oil which boils at 162-164 under 0.01 mm. pressure; 18 parts of morpholine, eugenol glycolic acid morpholide (B.P. 139-141 under 0.005 mm.v pressure),

4 I which melts at 62-64; 15 parts of pyrrolidine, eugenol glycolic acid pyrrolidide in the form of an oil (B.P..

129131 under 0.01 mm. pressure).

Example 4 50 parts of a 40% aqueous dimethylamine solution are diluted with parts of water and 24 parts of eugenol glycolic acid chloride are added dropwise-while stirring strongly and cooling to under 0. The reaction mixture is then stirred for some hours at room temperature, di-

luted with the same volume of water and ethered out. The ethereal solution is washed with water, then aqueous sodium carbonate solution and again with water, dried over sodium sulphate and the ether is evaporated off. On distilling in a Hickmann flask, eugenol glycolic acid dimethylamide is obtained as a thick oil which boils a 133-135 under 0.001 mmQpressure.

If instead of the aqueous dimethylamine solution a solution of 30 parts of diethylamine'in 100 parts of water is used, then by the same method, eugenol glycolic acid diethylamide which has already been described in Example 1 is obtained.

Example 5 I 24 parts of eugenol glycolic acid chloride and a solution as concentrated as possible of 9 parts of sodium biwhich has already been described in the previous example is obtained.

Example 6 15 parts of diethylamine are added dropwise while stirring and cooling with a cooling mixture to a solution of 24 parts of isoeugenol glycolic acid chloride in 100 parts by volume of abs. ether. The reaction mixtureis' theu After cooling, water is added, the ethereal phase is separated, washed boiled under reflux for half an hour.

methyl-isopropylamine, eugenol glycolic acid di-n-butyl-Q amide (B.P. 128131) or eugenol glycolic acid-N- methyl-isopropylamide (B.P. 143-145") is obtained. In the above reactions the same amount of abs. benzene can be used instead of ether. I V 7 Example 7 About 15 parts of ethylamine'are added to 25 parts of eugenol glycolic acid ethylester in 200 parts of ethanol and the whole is heated in a closed vessel for some hours at 40-50. The solvent is then distilled ofl and the crude eugenol glycolic acid ethylamide is recrystallised, e.g. from petroleum ether. v

Example 8 A solution of 30 parts of N-n-butyl aniline in 50 parts by volume of abs. ether is added dropwise while stirring and cooling with a cooling mixture to a solution of 24 which 1mm? l T V 4 38$ aft r thg distillation 75 parts of eugenol glycolic acid chloride-in parts by Eugenol glycolic acid-N-methyl anilide,

1311 175-178 Eugenol glycolic acid-N-ethyl anilide,

B.P. 139-142 Eugenol glycolic acid-N-n-propyl anilide,

B.P. 177-178 Eugenol glycolic acid-N-n-amyl anilide,

B.P. 125-130 Eugenol glycolic acid-N-n-hexyl anilide,

B.P. 145-150 Eugenol glycolic acid-N-allyl anilide,

B.P. 170-175 Eugenol glycolic acid-N-methallyl anilide,

B.P. 165170 Eugenol glycolic acid-N-ethyl-o-toluidide,

B.P. 165-167 Eugenol glycolic acid-N-ethyl-p-toluidide,

B.P. 173-176 Eugenol glycolic acidN-n-propyl-p-toluidide,

B.P. 167172 Eugenol glycolic acid-N-ethyl-3'.4'-dimethyl anilide,

, B.P. 175-180 Eugenol glycolic acid-N-methyl-p-chloranilide,

' B.P.o.o o5 168-173 Eugenol glycolic acid-N-ethyl-p-chloranilide,

M.P. 48-49 Eugenol glycolic acid-N-n-propyl-p-chloranilide,

M.P. 81-82 Eugenol glycolic acid-N-n-butyl-p-chlorani1ide,

M.P. 74-75 Eugenol glycolic acid-N-ethyl-3'.4'-dichloranilide,

' M.P. 70-71 Eugenol glycolic acid-N-ethyl-p-bromanilide,

B.P. 175-178 Eugenol glycolic acid-N-ethyl-p-anisidide,

I B.P. 157-163 I soeugenol glycolic acid-N-ethyl anilide,

B.P. 148-153 Isoeugenol glycolic acid-N-n-butyl anilide,

33. 150-152 The compounds according to the present invention produce general anaesthesia in man. For example, eugenol glycolic acid diethylamide, when administered by intra- 6 venous injection in a dosis of 2-5 mg. per kg., causes general anaesthesia. It shows a great advantage in that it does not depress the respiratory centre.

What we claim is: 1. u-(2-methoxy-4-allyl-phenoxy)-acetic acid N,N-diethylamide of the formula 56H; 2. a(2-methoxy-4-allyl-phenoxy)-acetic acid N-phenyl-N-n-propylamide of the formula CHFCH-CH OCH- 3. a-(2-methoxy-4-allyl-phenoxy)-acetic acid N-phenyl-N-n-butylamide of the formula om=on-on 0-0112-0 o-N phenyl ona 4. a-(2-methoxy-4-allyl-phenoxy)-acetic acid N-phenyl-N-allylamide of the formula CHr-CH=CH9 5. u-(2-methoxy-4-allyl-phenoxy)-acetic acid N-phenyl-N-methallylamide of the formula oHFon-on Qo-om-o 0-N\ hen 1 CH8 D y 6. a(2-methoxy-4-allyl-phenoxy)-acetic acid N-p-chlorophenyl-N-n-propyl-amide of the formula References Cited in the file of this patent UNITED STATES PATENTS 

1. A-(2-METHOXY-4-ALLYL-PHENOXY)-ACETIC ACID N,N-DIETHYLAMIDE OF THE FORMULA 